1. Field of the Invention
The present invention relates to an EBV antigen specific T-cell receptor which is capable of producing TCR-modified T cells specific for epitopes derived from a latent membrane protein 1 (LMP1) of an Epstein-Barr virus (EBV) and the use thereof.
2. Discussion of the Related Art
The number of patients clinically diagnosed as suffering from tumors has recently been increasing due to environmental changes, aging of the population, improvement in diagnostic technology, etc. However, it is difficult to perfectly remove tumors by just using the conventional palliative therapies for tumors because a micrometastatic tumor cell acquires a tolerance due to its genetic instability. Accordingly, there arises a need to develop new immunotherapies that help to overcome the limitations of conventional tumor therapies and an effective general-purpose method for the treatment of tumors using the same.
EBV belongs to the herpesvirus family, and 90% or more of normal people become infected with EBV. EBV is usually established by a latent infection without symptoms, but in patients whose immune system is impaired over a long period of time due to a bone marrow or organ transplant, EBV is known to cause cancer such as lymphoproliferative diseases, Burkitt's lymphoma, nasopharyngeal carcinoma (NPC), Hodgkin's disease, etc. Lymphocyte disorders associated with EBV infection include post-transplant lymphoproliferative diseases (PTLDs) that occur after transplantation in extranodal NK/T-cell lymphoma, nasal type, including Hodgkin's lymphoma. The lymphoproliferative disease, which is a non-Hodgkin's lymphoma type, is present with various manifestations ranging from benign diseases, such as polyclonal B-cell lymphocytosis, to malignant diseases, such as malignant lymphoma, as the proliferation of lymphocytes or plasma cells occurs as a result of EBV latency in the donor and the continued administration of immune inhibitors following solid organ or hematopoietic stem cell transplantation. The lymphoproliferative disease is a severe complication occurring throughout the whole body in 1-15% of organ transplant patients. It was recently confirmed that EBV genes are expressed in some patients with gastric cancer—in Japan and Korea, 5˜10% of patients with gastric cancer. A research team at the University of Kagoshima analyzed the distribution of EBV-positive gastric cancer in seven countries, including Japan, and found that the odds ratios of EBV-associated gastric cancer were higher in Russia (1.9), Colombia (2.5), Chile (2.7), etc., compared to that in Japan (1.0).
Conventional treatments of EBV-associated tumors include reduction of immune inhibitor administration, use of antiviral agents, anticancer chemotherapy, and administration of rituximab. However, responses to such conventional treatments vary and an effective treatment for EBV-associated tumors has not been found yet. Thus, it is urgent to develop a new treatment for EBV-associated tumors.
For adoptive immunotherapy using EBV antigen-specific T cells, Dr. Brenner's group conducted a study to find a method for treating EBV infections or EBV-associated tumors, such as EBV-associated lymphoma or throat cancer, by inducing CTLs specific for EBV antigens in vitro and transplanting hematopoietic stem cells. In Korea, the research group including the present inventors has succeeded initially in treating patients with EBV-positive lymphoma and acute leukemia using adoptive immunotherapy with antigen-specific T cells. The adoptive immunotherapy using antigen-specific T cells cultured in vitro would help to overcome the limitations of an antibody drug. However, despite such an advantage of the adoptive immunotherapy, the costs for culturing antigen-specific T cells with high avidity in vitro which recognize and remove tumor cells by overcoming immune tolerance to an tumor-associated antigen are highly expensive, which is hindering its clinical applications for general purposes and commercialization.
Recently, there has been a lot of research on targeted immunotherapy using gene-engineered T cells as adoptive immunotherapy to overcome the limitations of antibody drugs, cellular tumor vaccine, and adoptive cellular immunotherapy for treating tumor patients. In particular, it is expected that general-purpose targeted immunotherapy at the off-the-shelf stage which overcomes the limitations of tailor-made therapies can be developed by using TCRs specific for tumor antigens. However, due to difficulties in obtaining antigen-specific clones of T cells in order to obtain antigen-specific TCR genes and cloning the TCR genes, the development has only been modest in Korea and relevant clinical trials have been conducted by foreign researchers on a limited basis.